Pectin film compositions

ABSTRACT

The invention concerns, film-forming compositions containing pectin, at least one additional film-forming polymer and a setting system for use in pharmaceutical, veterinary, food, cosmetic or other products like films for wrapping food, aspics or jellies, preferably for predosed formulations like soft or hard capsules, as well as aqueous solutions of the composition for the manufacturing of said products.

This application claims priority from European Patent Application00402423.8, filed Sep. 1, 2000 and PCT Application PCT/EP01/09594, filedAug. 8, 2001.

The invention concerns film compositions containing pectin, at least oneadditional film-forming polymer and a setting system for use inpharmaceutical, veterinary, food, cosmetic or other products like filmsfor wrapping food, aspics or jellies, preferably for predosedformulations like soft or hard capsules.

Preferably pectin compositions are used for manufacturing of hardcapsules for pharmaceutical and veterinary applications. The pectincontent of the compositions confers enteric properties to such capsulesand at least one further film-forming polymer enhances the mechanicalperformance of the hard capsules. Combination with a setting systemallows use of the film-forming compositions of the invention forindustrial enteric capsule production by conventional dip mouldingprocesses.

The use of conventional dip moulding equipment for gelatin capsuleproduction allows the production of enteric capsules with equaldimensions and properties which can be used with conventional fillingequipment for gelatin capsules.

Enteric materials have a pH-dependent solubility. They are insolubleunder gastric conditions (simulated by a pH of 1.2) and readily solubleunder intestinal conditions (simulated by a pH of 6.8). Generally, thesematerials are polymers containing carboxylic groups, such as celluloseacetate phthalate (CAP), hydroxypropyl methylcellulose phthalate(HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC-AS),acrylic copolymers, pectin or alginates.

Usually enteric properties of pharmaceutical compositions are achievedby a coating process with enteric materials on e.g. granules, pellets,tablets or hard or soft capsules.

Enteric film compositions for hard capsules are described for example inU.S. Pat. No. 4,138,013. The film-forming composition for dip mouldingconsists of (1) hydroxypropyl methylcellulose and an ammonium salt ofcellulose acetate phthalate polymer or (2) of gelatin and an ammoniumsalt of a copolymer of methacrylic acid and methacrylic acid ester.However, it has been found that capsules made according to the mentionedtechniques have the disadvantages of poor solubility in intestinaljuice, high organic solvent content, inadequate stability and diffusionproblems.

Improvements are described in EP-A-0 056 825 with film compositionscontaining film-forming polymers like cellulose esters or celluloseether esters, plasticizers, viscosity-increasing substances like highlyviscous cellulose ethers, and anti-foaming agents.

Conventional hard capsules are produced from gelatin by a dip mouldingprocess. This process is based on the setting ability of hot gelatinsolution by cooling. On a totally automatic industrial hard gelatincapsule machine, mould pins are dipped into hot gelatin solution, thepins are removed from the solution, inverted, the gelatin solution (gel)remaining on the pins dried, stripped off the capsule shells and finallycap and body of the capsules cut and pre-joined. The immediate settingof the gelatin solution on the mould pins after dipping is the key stepin the process. Otherwise, the gelatin solution would flow down to formcapsules with non-uniform wall thickness and unacceptable properties.

A further enteric film composition consisting of a mixed ester of analkyl-, hydroxyalkyl- or hydroxyalkyl alkylcellulose esterified withsuccinyl anhydride and an aliphatic monocarboxylic acid anhydride isdescribed in U.S. Pat. No. 4,365,060. However, the solutions from thesecompositions do not possess any setting ability and therefore are notapplicable to industrial-scale dip moulding processes.

JP-A-58138458 describes a process for dipping mould pins into an aqueoussolution of hydroxypropyl-methyl-cellulose acetate succinate alkalimetal salt and gelatin and thereafter dipping in aqueous acid solution.However, in this composition the gelatin content is too low to providesufficient setting ability to the dipping solution.

Surprisingly, we have found that film compositions based on pectin asenteric material with at least a second film-forming material and asetting system have sufficient setting ability for industrial hardcapsule production.

Pectin has excellent enteric properties. A relatively low content ofpectin from 5 to 25%, preferably 10 to 20% by weight in the composition,is sufficient to obtain capsule films with enteric properties.Surprisingly, the capsule of the present invention can resistdissolution at least for 2 hours in in-vitro disintegration tests at pH1.2, and is easily soluble at pH 6.8 (>80% after 45 min under USPdissolution conditions).

The aqueous solutions of the film-forming compositions of the prior artare necessarily prepared under alkaline conditions and for this reasonare quite unstable. This disadvantage is overcome by the compositions ofthe invention because the pectin used as enteric material is watersoluble and consequently, the solution is quite stable.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 describes the results of the dissolution tests.

A further advantage of pectin is that pectin itself has the propertiesof a setting agent as described below.

A disadvantage of pectin is its brittleness like other entericmaterials, if it is used in film-forming compositions alone or in highamounts. Surprisingly, we have found that this problem could be solvedby the addition of at least one further film-forming material to thefilm-forming composition, which may be selected generally from allhydrosoluble film-forming materials of pharmaceutical and/or foodquality grade. Suitable are for example gelatin; pullulan; polyvinylalcohol; modified starches such as hydroxypropylated starch orhydroxyethylated starch; cellulose ethers such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethylcellulose or hydroxyethyl methylcellulose; and mixtures thereof.

Beside the improvement of the mechanical properties of the capsule filmthe addition of a second film-forming material also increases thecontent of solid material in the dip mould solution of the filmcomposition.

The content of pectin is in the range of 5 to 60%, preferably 10 to 40%,and that of the second film-forming material in the range of 40 to 95%,preferably 50 to 85% by weight in the film composition.

Low methoxyl pectins (LM pectins) with a degree of esterification of thecarboxyl groups with methanol below 50% are especially preferred.

The dipping solution for the capsule manufacturing process has a contentof the film-forming composition in the range of 15 to 40% by weight.

For the production of enteric capsules by an industrial dipping process,it is essential that the dipping solution has a sufficient settingability. Surprisingly, we have found that pectin, beside its entericproperties, can provide a sufficient setting behavior in the presence ofdivalent cations such as Ca⁺⁺ or Mg⁺⁺. The content of the divalent saltssuch as CaCl₂ in the dipping solution is preferably from 100 ppm to 5000ppm (0.01 to 0.5% by weight), this means an amount of from 0.04 to 2% byweight of the final film composition. During the preparation of thesolution, the formation of concentration peaks of the divalent salt hasto be avoided. High local concentrations of the divalent salt willresult in thermally irreversible local pectin gel formation.

The setting behavior of the film-forming solution of the invention maybe also achieved or altered by the addition of further gelling agents,preferably polysaccharides such as carrageenan or gellan. It has beenfound that addition of a small quantity of such additional gelling agentcan provide sufficient setting ability. The gelling agent content in thedipping solution is preferably from 0.05 to 2% by weight, this means anamount of from 0.2 to 8% by weight of the final film composition.

The temperature of the solution during the dipping process is alsoimportant for the setting properties of the dipping solution. Preferablythe temperature should be above 50° C., and is dependent on the pectincontent. It has been found that the temperature of the dipping solutionhas to be increased with higher pectin contents.

The inventive composition may contain in a further aspect additionalpharmaceutically or food-acceptable colouring agents in the range of 0to 10% based upon the weight of the final film composition.

The inventive composition may contain in a further aspect additionalpharmaceutically or food acceptable plasticizer or flavouring agents.

Finally, the inventive film-forming solution can be used for bandingenteric capsules. This prevents the capsule from leaking or separationof body and cap in gastric fluids.

The following examples and tests illustrate hard enteric capsuleproduction with the composition from the dipping solutions of theinvention and its enteric properties.

EXAMPLE 1

In 3.9 kg of deionised water at room temperature 2.5 g of CaCl₂ (0.05%by weight of the final dipping solution) and 100 g of glycerol(plasticizer, 2%) were dissolved, then 200 g of LM pectin (4%) and 800 gof hydroxypropyl starch (16%) dispersed. The mixture was then heated to95° C. to solubilize all components under stirring. After debubbling byreducing the stirring, the solution was equilibrated at 60° C.

The solution was poured into a dipping dish of a pilot machine ofconventional hard gelatin capsule production equipment. Keeping thedipping solution at 60° C., natural transparent hard enteric capsules ofsize 0 were produced according to the conventional process with the samedimensional specifications as the conventional hard gelatin capsules.The final capsules have a film composition of 16.3% pectin, 65.3%hydroxypropyl starch, 8.1% glycerol, 0.20% CaCl₂ and 10% moisture byweight.

EXAMPLE 2

200 g of LM pectin was dispersed into 2.0 kg of deionised water at roomtemperature, and then the mixture was heated to 85° C. to solubilize thepectin. After debubbling by reducing the stirring, the solution was thenequilibrated at 60° C.

2.5 kg of aqueous gelatin solution at 32% was prepared by conventionalmethod for hard gelatin capsule manufacture. 11.75 g of CaCl₂ aqueoussolution at 20% was added to the gelatin solution, which was thendebubbled by standing at 60° C.

The above two solutions were mixed together by gentle stirring to avoidcreating bubbles. The solution thus prepared (containing 4.25% pectin,17.0% gelatin and 0.05% CaCl₂ by weight) was then poured into a dippingdish of a pilot machine of conventional hard gelatin capsule productionequipment. Keeping the dipping solution at 45° C., natural transparenthard enteric capsules of size 0 were produced according to theconventional process with the same dimension specifications as theconventional hard gelatin capsules.

The final capsules have a film composition of 16.9% pectin, 67.4%gelatin, 0.20% CaCl₂ and 15.5% moisture by weight.

EXAMPLE 3

250 g of polyethyleneglycol 400, pre-heated at 60° C. was added undergentle stirring into 4.7 kg solution at 60° C., containing by weight4.25% pectin, 17.0% gelatin and 0.05% CaCl₂, prepared as in example 2.

Natural transparent enteric hard capsules were produced as in example 2.The final capsules have a film composition of 13.9% pectin, 55.8%gelatin, 17.4% PEG400 and 0.16% CaCl₂ and 12.7% moisture by weight.

EXAMPLE 4

3.85 g of gellan gum and 150 g of LM pectin were dispersed into 2.0 kgof deionised water at room temperature. The mixture was then heated to85° C. for solubilization. After debubbling, the solution was thenequilibrated at 60° C.

2.66 kg of aqueous gelatin solution containing 32% gelatin by weight wasprepared by conventional method for hard gelatin capsule manufacturingand equilibrated at 60° C.

The above two solutions were mixed and debubbled. The final solutioncontained 3.12% pectin, 17.7% gelatin and 0.08% gellan gum by weight.

Natural hard enteric capsules of size 0 were produced in the same manneras in the previous examples, keeping the dipping solution at 55° C. Thefinal capsules have a film composition of 12.8% pectin, 72.4% gelatinand 0.33% gellan gum and 14.5% moisture by weight.

All the capsules were evaluated for their enteric performance byin-vitro disintegration and dissolution tests according to the UPSXXIIII: first 2 hours in simulated gastric fluid (pH1.2) and then insimulated intestinal fluid (pH6.8). No enzyme was used in these tests.

The capsules were filled with lactose containing 0.1% of Indigotine(FD&C blue No2) for disintegration test or filled with acetaminophen forin-vitro dissolution test. Capsules were then banded with the samesolution used respectively during the capsule manufacture for eachexample. The capsule banding prevents separation of capsule cap and bodyduring the disintegration test.

The results of the disintegration tests are shown in Table 1 and theresults of the dissolution tests are shown in FIG. 1.

TABLE 1 Disintegration Results Disintegration time Capsule pH1.2 pH6.8Example 1 >2 h 10.6 min Example 2 >2 h 3.5 min Example 3 >2 h 2.5 minExample 4 >2 h 4.8 min

The tests performed confirmed the excellent gastric resistance of allcapsules, they remained intact even after 2 hours exposition to pH 1.2.

Capsules of examples 1–3 dissolved very quickly after passing into pH6.8 buffer solution. Capsules of example 4 showed some delay. The use ofan additional setting agent would be a possibility to modulate thedissolution profile under intestinal conditions.

1. An enteric capsule film composition consisting essentially: a) 5–60weight % pectin; b) 40–95 weight % of a second film-forming polymerselected from the group consisting of gelatin; pullulan; polyvinylalcohol; hydroxypropylated starch, hydroxyethylated starch;hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose,hydroxyethyl cellulose, hydroxyethyl methyl cellulose; or mixturesthereof; and c) a setting system comprising the pectin of part (a) incombination with (i) 0.04–2 weight % of a salt comprising a divalentcation; or (ii) 0.2–8 weight % of a polysaccharide selected from thegroup consisting of carrageenan, gellan and mixtures thereof; whereinthe capsule can resist dissolution for at least 2 hours at a PH of 1.2.2. A capsule according to claim 1 wherein the content of pectin is10–40%, and that of the second film-forming polymer is 50 to 85%.
 3. Acapsule according to claim 1 wherein the divalent cationic salts areselected from the group consisting of magnesium and calcium salts.
 4. Acapsule according to claim 1 additionally comprising at least oneadditional ingredient selected from the group consisting of coloringagents, plasticizers and flavoring agents.
 5. A method for making acapsule of claim 1 wherein the method is a dip molding process using asolution at a temperature of above 50 degrees C.
 6. A capsule as claimedin claim 1 wherein the second film-forming polymer is gelatin.
 7. Acapsule as claimed in claim 1 wherein the second film-forming polymer ishydroxypropyl methylcellulose.
 8. A capsule as claimed in claim 1wherein the second film-forming polymer is pullulan.